This invention relates to a stabilized preparation of a xcex2-lactam antibiotic having an esterified carboxy group directly coupled to the nucleus.
Since xcex2-lactam antibiotics, particularly penicillin antibiotics, are generally allergenic, it is common practice to have them granulated, for instance, to prevent scattering but the practice is not effective enough in preventing scattering. Therefore, the inventors of this invention explored the feasibility of formulating them into oil-containing preparations. However, there is the problem that xcex2-lactam antibiotics having an esterified carboxy group directly coupled to the nucleus are generally thermo-labile in oil-containing compositions.
This invention has been made to solve the above problem, with its object being to provide a stabilized preparation of a xcex2-lactam antibiotic having an esterified carboxy group directly coupled to the nucleus which is stable against heat even in an oil-including formulation.
The inventors of this invention did much research to overcome the above stability problem of xcex2-lactam antibiotics having an esterified carboxy group directly coupled to the nucleus and found for the first time that when a xcex2-lactam antibiotic having an esterified carboxy group directly coupled to the nucleus is mixed with a salt of phosphoric acid and oil, a dramatic improvement occurs in its stability.
This invention is carried into practice by mixing a xcex2-lactam antibiotic having an esterified carboxy group directly coupled to the nucleus with a salt of phosphoric acid and oil. While this mixing is carried out using a kneading-machine or the like, the resulting mixture is generally in the form of a paste. This paste can be put to use as it is but is preferably processed into various dosage forms in the routine manner.
The xcex2-lactam antibiotic having an esterified carboxy group directly coupled to the nucleus includes those antibiotics having an ester moiety comprising a group of the formula: 
(wherein R1 means hydrogen or a lower (C1xe2x80x94C6 ) alkyl group such as methyl, ethyl or the like, n means an integer of 0xcx9c3, R2 means a C1xe2x80x94C10 alkanoyl group (e.g. a lower (C1xe2x80x94C6) alkanoyl group such as acetyl, propionyl, butyryl, isobutyryl or the like)); a carboxymethyl group of the formula: 
(wherein R3 means hydrogen or a lower alkyl group such as methyl, ethyl or the like, R4 means a straight-chain or branched lower (C1xe2x80x94C6) alkyl group such as methyl, ethyl or the like); or a group of the formula: 
The xcex2-lactam antibiotic having an esterified carboxy group directly coupled to the nucleus includes carboxylic acid esters of penicillin and carboxylic acid esters of cephalosporin; for example, such antibiotics in the penicillin series as tobicillin, talampicillin, pivampicillin, becampicilin, pivmecillinam, bacmecillinam, lenampicillin, sultamicillin, etc. and such antibiotics in the cephalosporin series as cefotiam hexetil, cefetamet pivoxil, cefpodoxime proxetil, cefteram pivoxil and cefuroxime axetil, among others.
The oil may for example be a naturally-occurring fish oil or vegetable oil. As an alternative, it may be a synthetic oil such as silicone oil. More particularly, the vegetable oil includes soybean oil, linseed oil, sesame oil, corn oil, rapeseed oil, olive oil, caster oil, peanut oil, coconut oil, etc., and the fish oil includes sardine oil, salmon oil, mackerel oil, saury oil, liver oil (granulose shark, codfish, skipjack, Pacific flying squid, yellowtail), etc. Aside from the above, sperm oil (seiwhale, humpjack whale, fin whale, blackfish) may also be used. Among these, soybean oil of the composition defined in Japanese Pharmacopoeia is preferred.
On the other hand, as the salt of phosphoric acid, there can be mentioned alkaline earth metal salts of phosphoric acid, such as aluminum phosphate, barium phosphate (primary, secondary and tertiary), calcium phosphate (primary, secondary and tertiary), etc. and alkali metal salts of phosphoric acid, such as sodium phosphate (primary, secondary and tertiary). Among these, calcium phosphate and, in particular, tertiary calcium phosphate are conducive to particularly satisfactory results.
The stabilized preparation of the invention may be provided in the pasty form as mentioned above but is preferably used in the conventional pharmaceutical dosage forms such as powders, fine granules, granules, tablets, sugar-coated tablets, capsules, solutions and emulsions. Where necessary, the preparation may contain a diluent (excipient), a disintegrator (e.g. sucrose, lactose, starch, glucose, wheat bran, dextrin, crystalline cellulose, low-substitution-degree hydroxypropylcellulose, synthetic aluminum silicate, etc.), a binder (thickener) (e.g. cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, sodium alginate, polyethylene glycol, etc.), a coloring agent, a sweetener, a lubricant (e.g. magnesium stearate) and other additives.
It is also recommendable that the stabilized preparation of the invention be provided in the form of a powder prepared by mixing a xcex2-lactam antibiotic having an esterified carboxy group directly coupled to the nucleus with said salt of phosphoric acid, then mixing the resulting mixture with oil and a surfactant (the resulting preparation is a paste), and adding a diluent (excipient) such as lactose.
The surfactant mentioned just above includes polyglycerol fatty acid esters, sucrose fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid esters and polyoxyethylene-polyoxypropylene alkyl ethers, among others.
The recommended proportions of said xcex2-lactam antibiotic having an esterified carboxy group directly coupled to the nucleus, said oil and said salt of phosphoric acid in the stabilized preparation of the invention are 5xcx9c50% (weight %; the same applied hereinafter) of the xcex2-lactam antibiotic having an esterified carboxy group directly coupled to the nucleus, 1.5xcx9c60% of the oil, and not less than 1.5% of the salt of phosphoric acid.
The effect of the invention is now explained by way of the following test example.